Treatment for neurodegenerative diseases

ABSTRACT

A method of treating a neurodegenerative disease in a subject in need thereof comprises: (a) administering the subject an ornithine decarboxylase inhibitor such as alpha-difluoromethylornithine or a pharmaceutically acceptable salt or prodrug thereof in an amount effective to treat the disease; and concurrently (b) administering the subject a polyamine or a pharmaceutically acceptable salt or prodrug thereof in an amount effective to reduce damage to the gastroinestinal tract of the subject by the ornithine decarboxylase inhibitor.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 60/688,491, filed Jun. 8, 2005, and of U.S.Provisional Patent Application Ser. No. 60/722,152, filed Sep. 30, 2005,the disclosures of both of which are incorporated by reference herein intheir entirety.

This invention was made with U.S. Government Support under Grant No.AG19740 from the National Institutes of Health. The U.S. Government hascertain rights to this invention.

FIELD OF THE INVENTION The present invention concerns methods andcompositions useful for the treatment of neurodegenerative diseases.BACKGROUND OF THE INVENTION

The polyglutamine-repeat diseases, a group of at least eight disorders,result from the expression of mutant proteins having in common anexpanded polyglutamine domain. Huntington's disease (HD) is oneautosomal dominant polyglutamine-repeat disease. HD is a progressive,fatal neurodegenerative disorder that displays characteristic abnormalmotor functions, behavior changes and dementia. There are presently nosatisfactory treatments and there continues to be a need for new ways totreat neurodegenerative diseases such as HD.

SUMMARY OF THE INVENTION

A first aspect of the present invention is a method of treating aneurodegenerative disease in a subject in need thereof. The methodcomprises: (a) administering, preferably orally administering, thesubject an ornithine decarboxylase inhibitor such asalpha-difluoromethylornithine or a pharmaceutically acceptable salt orprodrug thereof in an amount effective to treat the disease; andconcurrently (b) administering, preferably orally administering, thesubject a polyamine or a pharmaceutically acceptable salt or prodrugthereof in an amount effective to reduce damage to the gastroinestinaltract of the subject caused by the ornithine decarboxylase inhibitor.

A second aspect of the present invention is a method of treating aneurodegenerative disease in a subject in need thereof. The methodcomprises simultaneously orally administering in a single oral doseformulation: (a) an ornithine decarboxylase inhibitor such asalpha-difluoromethylornithine or a pharmaceutically acceptable salt orprodrug thereof in an amount effective to treat the disease; and (b) apolyamine or a pharmaceutically acceptable salt or prodrug thereof in anamount effective to reduce damage to the gastroinestinal tract of thesubject caused by the ornithine decarboxylase inhibitor.

A third aspect of the invention is an oral dose formulation for treatinga neurodegenerative disease comprising or consisting essentially of, incombination: (a) an ornithine decarboxylase inhibitor such asalpha-difluoromethylornithine or a pharmaceutically acceptable salt orprodrug thereof in an amount effective to treat the disease; and (b) apolyamine or a pharmaceutically acceptable salt or prodrug thereof in anamount effective to reduce damage to the gastroinestinal tract of thesubject caused by the ornithine decarboxylase inhibitor. The formulationmay be in any suitable form, such as a tablet, capsule or liquid.

A further aspect of the present invention is the use of an active agentas described herein for the preparation of a medicament for carrying outa method of treatment as described herein.

In a particular embodiment of the invention, the methods of the presentinvention are useful in the treatment of Parkinson's disease.

The foregoing and other objects and aspects of the present invention areexplained in greater detail in the drawings herein and the specificationset forth below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the timeline and protocol of a demonstration of the presentinvention in Huntington's disease (HD) mice.

FIG. 2 shows Average survival is increased by treatment with DFMO andputrescine in HD mice compared to untreated HD mice, in accordance withFIG. 1 (Average increased survival=33%; Averaged increased mediansurvival=49%).

FIG. 3 shows the Kaplan-Meyer Survival curve for HD untreated-vs-HDtreated mice treated in accordance with FIG. 1.

FIG. 4 shows that rotorod motor function is better in DFMO treated HDmice treated in accordance with FIG. 1.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Neurodegenerative disease as used herein includes, for example,amyotrophic lateral sclerosis (or ALS), Parkinson's disease, multiplesclerosis, and expanded polyglutamine repeat diseases.

Expanded polyglutamine repeat diseases (or “polyglutamine repeatdiseases) with which the present invention is concerned include, but arenot limited to, Huntington's disease, dentatorubral pallidoluysianatrophy, spinobulbar muscular atrophy, and spinocerebellar ataxia types1, 2, 3, 6 and 7. See, e.g., U.S. Pat. No. 6,632,616 to Burke et al.

“Treat” as used herein refers to any type of treatment that imparts abenefit to a patient afflicted with a disease, including improvement inthe condition of the patient (e.g., in one or more symptoms), delay inthe progression of the disease, etc.

“Pharmaceutically acceptable” as used herein means that the compound orcomposition is suitable for administration to a subject to achieve thetreatments described herein, without unduly deleterious side effects inlight of the severity of the disease and necessity of the treatment.

“Concurrent administration” means sufficiently close in time to producea combined effect (that is, concurrently may be two or more eventsoccurring within a short time period before or after each other).Concurrently is inclusive of “simultaneous.”

“Simultaneous administration” as used herein means that the activecompounds are administered at the same point in time or immediatelyfollowing one another. In the latter case, the two compounds areadministered at times sufficiently close that the results observed areindistinguishable from those achieved when the compounds areadministered at the same point in time.

“Chronic administration” as used herein refers to administration over aprolonged period of time, as opposed to acute administration in whichadministration is terminated when a disease is sufficiently treated orcured. For example, chronic administration may be administrationmultiple times a week (e.g., one, two or three times daily for three,four, five, six, or seven days a week) for a period of at least one,two, three, four, five or six months or more, after which time diseaseprogression is reassesed by the treating physician and dosage iscontinued or adjusted as necessary, with treatment typically continuingon an ongoing basis.

“Pharmaceutically acceptable prodrugs” as used herein refers to thoseprodrugs of the compounds of the present invention which are, within thescope of sound medical judgment, suitable for use in contact with thetissues of humans and lower animals without undue toxicity, irritation,allergic response and the like, commensurate with a reasonablerisk/benefit ratio, and effective for their intended use, as well as thezwitterionic forms, where possible, of the compounds of the invention.

The present invention is primarily concerned with the treatment of humansubjects, but the invention may also be carried out on animal subjects,particularly mammalian subjects such as mice, rats, dogs, cats,livestock and horses for veterinary purposes, and for drug screening,testing and development purposes.

The disclosures of all United States Patent references cited herein areincorporated by reference herein in their entirety.

1. Active Compounds.

Ornithine decarboxylase inhibitors are known and described in, forexample, U.S. Pat. Nos. 5,753,714; 5,132,293; 5,002,879; 4,720,489; and4,499,072. Examples include, but are not limited to,alpha-difluoromethylornithine, 2-(difluoromethyl)-2,5-diaminopentanoicacid; alpha-ethynyl ornithine; 6-heptyne-2,5-diamine; 2-methyl-6-heptynediamine; alpha.-difluoromethyl ornithine; the methyl ester ofmonofluoromethyl dehydroornithine; the R,R-isomer of methyl acetylenicputrescine, 3-aminooxy-1-aminopropane (APA) and its analogs orderivatives such as CGP 52622A and CGP 54169A,1,25-dihydroxycholecalciferol, and pharmaceutically acceptable salts andprodrugs thereof.

Additional examples of ornithine decarboxylase inhibitors that may beused to carry out the present invention include but are not limited to:Drug Company CGP-52622A Novartis AG CGP-54169A Novartis AGdihydroxycholecalciferol Chugai Pharmaceutical Co Ltd insulin analogs,Scios/Pfizer Scios Inc CGP-51905A Novartis AG CGP-45300A Novartis AGanticancer agents, University of University of Illinois Illinois vitaminD analogs (cancer), Johns Hopkins University Cytochroma/Johns Hopkins

Alpha-difluoromethylornithine (DFMO; eflornithine (sometimes called“elfornithine”) is known and described in, for example, U.S. Pat. Nos.6,730,809; 6,573,290; 6,258,845; and 4,925,835.

Polyamines useful for carrying out the present invention are known anddescribed in U.S. Pat. Nos. 6,867,237; 6,794,414; 6,368,598; and5,885,982. Polyamines may be primary amines, including C1-C5 alkylamines. Examples of suitable polyamines include but are not limited tospermine, spermidine, putrescine (1,4-diamino-butane),1,3-diamino-propane, 1,7-diamino-heptane, and 1,8-diamino-octane.

The active compounds disclosed herein can, as noted above, be preparedin the form of their pharmaceutically acceptable salts. Pharmaceuticallyacceptable salts are salts that retain the desired biological activityof the parent compound and do not impart undesired toxicologicaleffects. Examples of such salts are (a) acid addition salts formed withinorganic acids, for example hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, nitric acid and the like; and saltsformed with organic acids such as, for example, acetic acid, oxalicacid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconicacid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid,palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonicacid, methanesulfonic acid, p-toluenesulfonic acid,naphthalenedisulfonic acid, polygalacturonic acid, and the like; (b)salts formed from elemental anions such as chlorine, bromine, andiodine, and (c) salts derived from bases, such as ammonium salts, alkalimetal salts such as those of sodium and potassium, alkaline earth metalsalts such as those of calcium and magnesium, and salts with organicbases such as dicyclohexylamine and N-methyl-D-glucamine.

Prodrugs of active compounds as noted above are in general compoundsthat are rapidly transformed in vivo to yield the desired active agent.A thorough discussion is provided in T. Higuchi and V. Stella, Prodrugsas Novel delivery Systems, Vol. 14 of the A.C.S. Symposium Series and inEdward B. Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated by reference herein. See also U.S. Pat. No. 6,680,299Examples include a prodrug that is metabolized in vivo by a subject toan active drug having an activity of active compounds as describedherein, wherein the prodrug is an ester of an alcohol or carboxylic acidgroup, if such a group is present in the compound; an acetal or ketal ofan alcohol group, if such a group is present in the compound; anN-Mannich base or an imine of an amine group, if such a group is presentin the compound; or a Schiff base, oxime, acetal, enol ester,oxazolidine, or thiazolidine of a carbonyl group, if such a group ispresent in the compound, such as described in U.S. Pat. Nos. 6,680,324and 6,680,322.

2. Formulations and Administration.

The active compounds described above may be formulated foradministration in a pharmaceutical carrier in accordance with knowntechniques. See, e.g., Remington, The Science And Practice of Pharmacy(9^(th) Ed. 1995). In the manufacture of a pharmaceutical formulationaccording to the invention, the active compound (including thephysiologically acceptable salts thereof) is typically admixed with,inter alia, an acceptable carrier. The carrier must, of course, beacceptable in the sense of being compatible with any other ingredientsin the formulation and must not be deleterious to the patient. Thecarrier may be a solid or a liquid, or both, and is preferablyformulated with the compound as a unit-dose formulation, for example, atablet, which may contain from 0.01 or 0.5% to 95% or 99% by weight ofthe active compound. One or more active compounds may be incorporated inthe formulations of the invention, which may be prepared by any of thewell known techniques of pharmacy comprising admixing the components,optionally including one or more accessory ingredients.

The formulations of the invention include those suitable for oraladministration, although the most suitable route in any given case willdepend on the nature and severity of the condition being treated and onthe nature of the particular active compound which is being used.

Formulations suitable for oral administration may be presented indiscrete units, such as capsules, cachets, lozenges, or tablets, eachcontaining a predetermined amount of the active compound; as a powder orgranules; as a solution or a suspension in an aqueous or non-aqueousliquid; or as an oil-in-water or water-in-oil emulsion. Suchformulations may be prepared by any suitable method of pharmacy whichincludes the step of bringing into association the active compound and asuitable carrier (which may contain one or more accessory ingredients asnoted above). In general, the formulations of the invention are preparedby uniformly and intimately admixing the active compound with a liquidor finely divided solid carrier, or both, and then, if necessary,shaping the resulting mixture. For example, a tablet may be prepared bycompressing or molding a powder or granules containing the activecompound, optionally with one or more accessory ingredients. Compressedtablets may be prepared by compressing, in a suitable machine, thecompound in a free-flowing form, such as a powder or granules optionallymixed with a binder, lubricant, inert diluent, and/or surfaceactive/dispersing agent(s). Molded tablets may be made by molding, in asuitable machine, the powdered compound moistened with an inert liquidbinder.

Capsules may contain particles coated with the active agents. Particlesused herein may be of any suitable size, typically from about 100 to1000 micrometers in diameter. Examples include particles with a diameterof about 600 to 250 um (30-60 mesh), or a diameter of 700 to 600 um(25-30 mesh). Size of particles can be determined in accordance withknown techniques, such as described in the CRC Handbook, 64^(th)edition, page F-114 and USP24/NF19, page 1969. Any suitable corematerial can be used for the particles. Examples of such materials arepolymers e.g., plastic resins; inorganic substances, e.g., silica,glass, hydroxyapatite, salts (sodium or potassium chloride, calcium ormagnesium carbonate) and the like; organic substances, e.g., activatedcarbon, acids (citric, fumaric, tartaric, ascorbic and the like acids),and saccharides and derivatives thereof. Particularly suitable materialsare saccharides such as sugars, oligosaccharides, polysaccharides andtheir derivatives, for example, glucose, rhamnose, galactose, lactose,sucrose, mannitol, sorbitol, dextrin, maltodextrin, cellulose,microcrystalline cellulose, sodium carboxymethyl cellulose, starches(maize, rice, potato, wheat, tapioca) and the like saccharides. Inaddition, the particles according to the present invention may furthercontain one or more additional additives such as thickening agents,lubricants, surfactants, preservatives, complexing and chelating agents,electrolytes or other active ingredients, e.g., antiinflammatory agents,antibacterials, disinfectants or vitamins. The particles may be insertedinto a suitable capsule such as a gelatin capsule in accordance withknown techniques.

Tablets can be produced by conventional tabletting techniques withconventional ingredients or excipients. The tablets are preferablyformed from a composition comprising the particles described hereindistributed in a mixture of a disintegrant and a diluent or filler.Suitable disintegrants include, but are not limited to, crospovidone andcroscarmellose. Suitable diluents include, but are not limited to,lactose, sucrose, dextrose, mannitol, sorbitol, starch, cellulose,calcium phosphate, microcrystalline celulose such as AVICEL™, etc.Tablets may include a variety of other conventional ingredients, such asbinders, buffering agents, lubricants, glidants, thickening agents,sweetening agents, flavors, and pigments.

Liquids can be prepared in any suitable form, such as a syrup, inaccordance with known techniques by dissolving, solubilizing orsuspending (e.g., as an emulsion or microemulsion) the active agentstherein. Such liquids may be aqueous liquids, optionally includingadditional cosolvents such as oils and the like.

The therapeutically effective dosage of any one active agent, the use ofwhich is in the scope of present invention, will vary somewhat fromcompound to compound, and patient to patient, and will depend uponfactors such as the age and condition of the patient and the route ofdelivery. Such dosages can be determined in accordance with routinepharmacological procedures known to those skilled in the art. Ingeneral, the alpha-difluoromethylornithine is included in theformulation or administered to the subject in an amount effective todeliver a dosage thereof of 0.1 or 0.5 grams per meter² per day to thesubject, up to 2, 3 or 5 grams per meter² per day to the subject. Ingeneral, the polyamine is included in said formulation or administeredto the subject in an amount effective to deliver a dosage thereof of 20,50 or 100 mg per kg per day to the subject, up to 1000 or 2000 mg per kgper day to the subject.

The present invention is explained in greater detail in the followingnon-limiting Examples.

EXAMPLE 1

Huntington's disease (HD) mice are transgenic mice that express a cDNAencoding an N-terminal fragment (171 amino acids) of huntingtin with 88glutamine repeats. HD mice are known. See, e.g., G. Schilling et al.,Intranuclear inclusions and neuritic aggregates in transgenic miceexpressing a mutant N-terminal fragment of huntingtin, Hum. Mol. Genet8(3), 397-407 (1999).

This example was carried out as schematically illustrated in FIG. 1.Briefly, experimental HD mice (n=12) were administered DFMO (0.3%) plusputrescine (0.1%) added to their drinking water for a period beginning72 days after birth through 81 (199) days after birth or until death ofthe animal. Control HD mice received the same food and water but withoutadded DFMO plus putrescine. Control wild-type mice received DFMO plusputrescine in like manner as the experimental mice.

As shown in FIG. 2, the average survival of HD receiving experimentalmice (right bar) was substantially increased as compared untreated HDmice (left bar). The average increased survival was 33% and the averagedincreased median survival was 49%) Likewise, FIG. 3 shows that theKaplan-Meyer Survival curve for HD untreated-vs-HD treated mice, withthe curve substantially improved for the treated mice.

As shown in FIG. 4, motor function, as determined by the rotorod test,was improved in DFMO plus putrescine treated HD (circles) mice ascompared to untreated HD mice (squares) at both day 93 and day 105 afterbirth (with day 93 being more than 10 days after the treatment periodhad ended).

EXAMPLE 2 Parkinson's Disease

Parkinson's disease (PD) is characterized by the presence of aggregates(Lewy bodies) composed of alpha-synculein and other cellular proteinswithin neurons. (Paleologou; Gandhi) These aggregates are believed to bea critical factor in the death of the neuron and in the etiology of PD(Paleologou; Schrag). Mutated alpha-synuclein, as observed in thoseindividuals with familial PD caused by synculein mutations, causesincreased aggregate formation (Paleologou). A cell culture model is usedto study alpha-synuclein aggregate formation in vitro. This model wascreated by using molecular biological techniques to transfect adopaminergic cell line with DNA constructs that, when expressed,generate large amounts of normal alpha-synuclein (over-expressed) ormutated human alpha synuclein within the cells essentially as describedby Perez et al (Perez). A control cell line was also generated that wastransfected with empty vector, ie, did not express mutated alphasynuclein. These cells were then treated with Difluoromethylornithine(DFMO) to test the ability of this agent to reduce cell death.

As shown in Table 1, when compared to cells with empty vector only(Control cells), cells over-expressing alpha synuclein or expressingmutated alpha synuclein showed increased cell death. Compared to controlcells, treatment with DFMO (100-500 uM) increased survival in cellsover-expressing alpha synuclein and in cells expressing mutated alphasynuclein by up to 54%. Since the cells that die in humans with PD aredopaminergic neurons (that is, use dopamine as their neurotransmitter),these data from a dopaminergic neuronal cell line provide evidence thatDFMO is efficacious in reducing neuronal death. TABLE 1 % Dead Cells %rescue minus compared to % Dead % Dead % DFMO- vector control CellsCells treated cells^(#) for DFMO Construct (untreated) (DFMO) (100 um)treated cells Vector only 39.8% 30.2 9.6% Alpha- 44.8 29.8  15% 54%synuclein* Mutated alpha 51.6 38.1 13.5 40% synuclein**#Represents % cells rescued by DFMO.*Human alpha synuclein (wild type) cDNA was amplified by polymerasechains reaction (PCR) and cloned into pcDNA 3.1 vector (purchased fromInvitrogen). HA tag was fused to the alpha synculein C-terminus byadding the HA sequence in the PCR reverse primer. Cells were transfectedwith Fugene 6 Transfection Reagent (purchased from Roche AppliedScience) and co-transfected with# synphilin-1 plasmid (gift of Dr. Pamela McLean, Mass General HospitalEast). Estimated transfection efficiency = 20%**Human A53T alpha-synuclein mutant and wild type alpha-synuclein wereamplified by PCR and cloned into pEGFP-N2 vector (purchased fromClontech) to make a fusion protein. Cells were transfected as above.MN9D cells were provided by Ruth Perez (University of Pittsburg) andwere originally made by Alfred Heller and Lisa Won, University ofChicago.Cell death was determined using Propidium iodide and cells counted usingflow cytometry.References:

Schrag A, Schott J M. Lancet Neurol. 2006 April; 5(4):355-63Epidemiological, clinical, and genetic characteristics of early-onsetparkinsonism.

Paleologou K E, Irvine G B, El-Agnaf O M. Biochem Soc Trans. 2005November; 33(Pt 5):1106-10 Alpha-synuclein aggregation inneurodegenerative diseases and its inhibition as a potential therapeuticstrategy.

Gandhi S, Wood N W. Hum Mol Genet. 2005 Oct. 15; 14 Molecularpathogenesis of Parkinson's disease.

Perez R G, Waymire J C, Lin E, Liu J J, Guo F, Zigmond M J. J Neurosci.2002 Apr. 15; 22(8):3090-9. A role for alpha-synuclein in the regulationof dopamine biosynthesis.

The foregoing is illustrative of the present invention, and is not to beconstrued as limiting thereof. The invention is defined by the followingclaims, with equivalents of the claims to be included therein.

1. A method of treating a neurodegenerative disease in a subject in needthereof, comprising: (a) orally administering said subject an ornithinedecarboxylase inhibitor or a pharmaceutically acceptable salt or prodrugthereof in an amount effective to treat said disease; and concurrently(b) orally administering said subject a polyamine or a pharmaceuticallyacceptable salt or prodrug thereof in an amount effective to reducedamage to the gastroinestinal tract of said subject by said ornithinedecarboxylase inhibitor or pharmaceutically acceptable salt or prodrugthereof.
 2. The method of claim 1, wherein said subject is a humansubject.
 3. The method of claim 1, wherein said neurological disease isa polyglutamine repeat disease.
 4. The method of claim 4, wherein saidpolyglutamine repeat disease is selected from the group consisting ofHuntington's disease, dentatorubral pallidoluysian atrophy, spinobulbarmuscular atrophy, and spinocerebellar ataxia types 1, 2, 3, 6 and
 7. 5.The method of claim 1, wherein said neurodegenerative disease is aamyotrophic lateral sclerosis.
 6. The method of claim 1, wherein saidornithine decarboxylase inhibitor is alpha-difluoromethylornithine or apharmaceutically acceptable salt or prodrug thereof.
 7. The method ofclaim 1, wherein said polyamine is selected from the group consisting ofspermine, spermidine, putrescine (1,4-diamino-butane),1,3-diamino-propane, 1,7-diamino-heptane, and 1,8-diamino-octane.
 8. Themethod of claim 1, wherein said administering steps are carried outchronically for at least six months.
 9. The method of claim 1, whereinsaid administering steps are carried out chronically for at least oneyear.
 10. A method of treating a neurodegenerative disease in a subjectin need thereof, comprising simultaneously orally administering in asingle oral dose formulation: (a) an ornithine decarboxylase inhibitoror a pharmaceutically acceptable salt or prodrug thereof in an amounteffective to treat said disease; and (b) a polyamine or apharmaceutically acceptable salt or prodrug thereof in an amounteffective to reduce damage to the gastroinestinal tract of said subjectby said ornithine decarboxylase inhibitor.
 11. The method of claim 10,wherein said subject is a human subject.
 12. The method of claim 10,wherein said neurodegenerative disease is a polyglutamine repeatdisease.
 13. The method of claim 11, wherein said polyglutamine repeatdisease is selected from the group consisting of Huntington's disease,dentatorubral pallidoluysian atrophy, spinobulbar muscular atrophy, andspinocerebellar ataxia types 1, 2, 3, 6 and
 7. 14. The method of claim10, wherein said neurodegenerative disease is a amyotrophic lateralsclerosis.
 15. The method of claim 10, wherein said ornithinedecarboxylase inhibitor is alpha-difluoromethylornithine or apharmaceutically acceptable salt or prodrug thereof.
 16. The method ofclaim 10, wherein said polyamine is selected from the group consistingof spermine, spermidine, putrescine (1,4-diamino-butane),1,3-diamino-propane, 1,7-diamino-heptane, and 1,8-diamino-octane. 17.The method of claim 10, wherein said administering step is a chronicadministering step.
 18. The method of claim 10, wherein saidadministering step is carried out chronically for at least six months.19. The method of claim 10, wherein said administering step is carriedout chronically for at least one year.
 20. An oral dose formulation fortreating a neurodegenerative disease comprising, in combination: (a) anornithine decarboxylase inhibitor or a pharmaceutically acceptable saltor prodrug thereof in an amount effective to treat said disease; and (b)a polyamine or a pharmaceutically acceptable salt or prodrug thereof inan amount effective to reduce damage to the gastroinestinal tract ofsaid subject by said ornithine decarboxylase inhibitor orpharmaceutically acceptable salt or prodrug thereof.
 21. The formulationof claim 20, wherein said ornithine decarboxylase inhibitor isalpha-difluoromethylornithine or a pharmaceutically acceptable salt orprodrug thereof.
 22. The formulation of claim 20, wherein said polyamineis selected from the group consisting of spermine, spermidine,putrescine (1,4-diamino-butane), 1,3-diamino-propane,1,7-diamino-heptane, and 1,8-diamino-octane.
 23. The formulation ofclaim 20, wherein: said ornithine decarboxylase inhibitor orpharmaceutically acceptable salt thereof is included in said formulationin an amount effective to deliver a dosage thereof of 0.1 to 5 grams permeter² per day to said subject; and said polyamine is included in saidformulation in an amount effective to deliver a dosage thereof of 20 to2000 mg per kg per day to said subject.
 24. The formulation of claim 20in the form of a tablet.
 25. The formulation of claim 20 in the form ofa capsule.
 26. The formulation of claim 20 in the form of a liquid. 27.A method of treating Parkinson's disease in a subject in need thereof,comprising: (a) orally administering said subject an ornithinedecarboxylase inhibitor or a pharmaceutically acceptable salt or prodrugthereof in an amount effective to treat said Parkinson's disease; andconcurrently (b) orally administering said subject a polyamine or apharmaceutically acceptable salt or prodrug thereof in an amounteffective to reduce damage to the gastroinestinal tract of said subjectby said ornithine decarboxylase inhibitor or pharmaceutically acceptablesalt or prodrug thereof.
 28. The method of claim 27, wherein saidsubject is a human subject.
 29. The method of claim 27, wherein saidornithine decarboxylase inhibitor is alpha-difluoromethylornithine or apharmaceutically acceptable salt or prodrug thereof.
 30. The method ofclaim 27, wherein said polyamine is selected from the group consistingof spermine, spermidine, putrescine (1,4-diamino-butane),1,3-diamino-propane, 1,7-diamino-heptane, and 1,8-diamino-octane. 31.The method of claim 27, wherein said administering steps are carried outchronically for at least six months.
 32. The method of claim 27, whereinsaid administering steps are carried out chronically for at least oneyear.
 33. A method of treating Parkinson's disease in a subject in needthereof, comprising simultaneously orally administering in a single oraldose formulation: (a) an ornithine decarboxylase inhibitor or apharmaceutically acceptable salt or prodrug thereof in an amounteffective to treat said Parkinson's disease; and (b) a polyamine or apharmaceutically acceptable salt or prodrug thereof in an amounteffective to reduce damage to the gastroinestinal tract of said subjectby said ornithine decarboxylase inhibitor.
 34. The method of claim 33,wherein said subject is a human subject.
 35. The method of claim 33,wherein said ornithine decarboxylase inhibitor isalpha-difluoromethylornithine or a pharmaceutically acceptable salt orprodrug thereof.
 36. The method of claim 33, wherein said polyamine isselected from the group consisting of spermine, spermidine, putrescine(1,4-diamino-butane), 1,3-diamino-propane, 1,7-diamino-heptane, and1,8-diamino-octane.
 37. The method of claim 33, wherein saidadministering step is a chronic administering step.
 38. The method ofclaim 33, wherein said administering step is carried out chronically forat least six months.
 39. The method of claim 33, wherein saidadministering step is carried out chronically for at least one year.